Interplay between acetylation and ubiquitination of imitation switch chromatin remodeler Isw1 confers multidrug resistance in Cryptococcus neoformans.
Interplay between acetylation and ubiquitination of imitation switch chromatin remodeler Isw1 confers multidrug resistance in Cryptococcus neoformans.
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作者：
Meng Y;Ni Y;Li Z;Jiang T;Sun T;Li Y;Gao X;Li H;Suo C;Li C;Yang S;Lan T;Liao G;Liu T;Wang P;Ding C
新型隐球菌对人类健康构成威胁，但抗隐球菌治疗因耐药性的出现而受阻，其潜在机制仍知之甚少。在此，我们发现Isw 1，一个模仿开关染色质重塑ATP酶，作为一个主调节基因负责在体内和体外多药耐药的C。新人类ISW 1基因被破坏的细胞对多种抗真菌药物表现出强烈的耐药性。质谱分析显示Isw 1是乙酰化和泛素化的，这表明这两个修饰事件之间存在相互作用来控制Isw 1的功能。乙酰化和泛素化位点的突变研究表明，Isw 1 K97的乙酰化状态与Isw 1 K113和Isw 1 K441的泛素化过程协调，通过调节Isw 1和Cdc 4（一种E3连接酶）之间的相互作用。此外，临床分离的C.过表达耐降解ISW 1 K97 Q等位基因的新生儿表现出受损的耐药表型。总的来说，我们的研究揭示了一个复杂的乙酰化-Isw 1-泛素化调节轴，控制C.新人类
Cryptococcus neoformans poses a threat to human health, but anticryptococcal therapy is hampered by the emergence of drug resistance, whose underlying mechanisms remain poorly understood. Herein, we discovered that Isw1, an imitation switch chromatin remodeling ATPase, functions as a master modulator of genes responsible for in vivo and in vitro multidrug resistance in C. neoformans. Cells with the disrupted ISW1 gene exhibited profound resistance to multiple antifungal drugs. Mass spectrometry analysis revealed that Isw1 is both acetylated and ubiquitinated, suggesting that an interplay between these two modification events exists to govern Isw1 function. Mutagenesis studies of acetylation and ubiquitination sites revealed that the acetylation status of Isw1K97 coordinates with its ubiquitination processes at Isw1K113 and Isw1K441 through modulating the interaction between Isw1 and Cdc4, an E3 ligase. Additionally, clinical isolates of C. neoformans overexpressing the degradation-resistant ISW1K97Q allele showed impaired drug-resistant phenotypes. Collectively, our studies revealed a sophisticated acetylation–Isw1–ubiquitination regulation axis that controls multidrug resistance in C. neoformans.
影响因子：
14.9
作者：
通讯作者：
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DNA循环有助于靶向染色质重塑酶。
影响因子：
16
作者：
Yadon, Adam N.;Singh, Badri Nath;Hampsey, Michael;Tsukiyama, Toshio
通讯作者：
Tsukiyama, Toshio
影响因子：
3.7
作者：
Yu, Shuying;Paderu, Padmaja;Lee, Annie;Eirekat, Sami;Healey, Kelley;Chen, Liang;Perlin, David S.;Zhao, Yanan
通讯作者：
Zhao, Yanan